HYDROCODONE/IBU 7.5/200mg

Hydrocodone Bitartrate and Ibuprofen Tablets are indicated for the short-term management of acute pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate.

Limitations of Use
Carefully consider the potential benefits and risks of Hydrocodone Bitartrate and Ibuprofen Tablets and other treatment options before deciding to use Hydrocodone Bitartrate and Ibuprofen Tablets Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals (see WARNINGS: Cardiovascular Thrombotic Events, Gastrointestinal Bleeding, Ulceration, and Perforation ). Do not use Hydrocodone Bitartrate and Ibuprofen Tablets for the treatment of conditions such as osteoarthritis or rheumatoid arthritis.
Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses (see WARNINGS: Addiction, Abuse, and Misuse ), reserve Hydrocodone Bitartrate and Ibuprofen Tablets for use in patients for whom alternative treatment options (e.g., non-opioid analgesics):
•   Have not been tolerated, or are not expected to be tolerated,
•   Have not provided adequate analgesia, or are not expected to provide adequate analgesia

Carefully consider the potential benefits and risks of hydrocodone bitartrate and ibuprofen tablets and other treatment options before deciding to use Hydrocodone Bitartrate And Ibuprofen Tablets. Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals (see WARNINGS: Cardiovascular Thrombotic Events, Gastrointestinal Bleeding, Ulceration, and Perforation ).

Initiate the dosing regimen for each patient individually, taking into account the patient's severity of pain, patient response, prior analgesic treatment experience, and risk factors for addiction, abuse, and misuse (see WARNINGS: Addiction, Abuse, and Misuse ).

Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy and following dosage increases with hydrocodone bitartrate and ibuprofen tablets and adjust the dosage accordingly (see WARNINGS: Life-Threatening Respiratory Depression ).

After observing the response to initial therapy with Hydrocodone Bitartrate and Ibuprofen Tablets, the dose and frequency should be adjusted to suit an individual patient's needs.

Initial Dosage

For the short-term (generally less than 10 days) management of acute pain, the recommended dose of hydrocodone bitartrate and ibuprofen tablets are one tablet every 4 to 6 hours, as necessary. Dosage should not exceed 5 tablets in a 24-hour period. It should be kept in mind that tolerance to hydrocodone can develop with continued use and that the incidence of untoward effects is dose related.

The lowest effective dose or the longest dosing interval should be sought for each patient (see WARNINGS ), especially in the elderly. After observing the initial response to therapy with Hydrocodone Bitartrate and Ibuprofen Tablets, the dose and frequency of dosing should be adjusted to suit the individual patient's need, without exceeding the total daily dose recommended.

Titration and Maintenance of Therapy

Individually titrate Hydrocodone Bitartrate and Ibuprofen Tablets to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving Hydrocodone Bitartrate and Ibuprofen Tablets to assess the maintenance of pain control and the relative incidence of adverse reactions, as well as monitoring for the development of addiction, abuse, or misuse (see WARNINGS: Addiction, Abuse, and Misuse ). Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration.

If the level of pain increases after dosage stabilization, attempt to identify the source of increased pain before increasing the Hydrocodone Bitartrate and Ibuprofen Tablets dosage. If unacceptable opioid-related adverse reactions are observed, consider reducing the dosage. Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions.

Discontinuation of Hydrocodone Bitartrate and Ibuprofen Tablets

When a patient who has been taking Hydrocodone Bitartrate and Ibuprofen Tablets regularly and may be physically dependent no longer requires therapy with Hydrocodone Bitartrate and Ibuprofen Tablets, taper the dose gradually, by 25% to 50% every 2 to 4 days, while monitoring carefully for signs and symptoms of withdrawal. If the patient develops these signs or symptoms, raise the dose to the previous level and taper more slowly, either by increasing the interval between decreases, decreasing the amount of change in dose, or both. Do not abruptly discontinue Hydrocodone Bitartrate and Ibuprofen Tablets in a physically dependent patient (see WARNINGS: Addiction, Abuse, and Misuse, DRUG ABUSE AND DEPENDENCE ).

Inhibitors of CYP3A4 and CYP2D6

The concomitant use of hydrocodone bitartrate and ibuprofen tablets and CYP3A4 inhibitors, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir), can increase the plasma concentration of hydrocodone, resulting in increased or prolonged opioid effects. These effects could be more pronounced with concomitant use of hydrocodone bitartrate and ibuprofen tablets and CYP2D6 and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of hydrocodone bitartrate and ibuprofen tablets are achieved (see WARNINGS: Risks of Concomitant Use or Discontinuation of Cytochrome P450 3A4 Inhibitors and Inducers ).

After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the hydrocodone plasma concentration will decrease (see CLINICAL PHARMACOLOGY: Pharmacokinetics ), resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to Hydrocodone Bitartrate and Ibuprofen Tablets.

If concomitant use is necessary, consider dosage reduction of hydrocodone bitartrate and ibuprofen tablets until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider a dosage increase of hydrocodone bitartrate and ibuprofen tablets until stable drug effects are achieved. Monitor for signs of opioid withdrawal.

CYP3A4 Inducers

The concomitant use of hydrocodone bitartrate and ibuprofen tablets and CYP3A4 inducers, such as rifampin, carbamazepine, and phenytoin, can decrease the plasma concentration of hydrocodone (see CLINICAL PHARMACOLOGY: Pharmacokinetics ), resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to hydrocodone (see WARNINGS: Withdrawal ).

After stopping a CYP3A4 inducer, as the effects of the inducer decline, the hydrocodone plasma concentration will increase (see CLINICAL PHARMACOLOGY: Pharmacokinetics ), which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression.

If concomitant use is necessary, consider a dosage increase of hydrocodone bitartrate and ibuprofen tablets until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider hydrocodone bitartrate and ibuprofen tablets dosage reduction and monitor for signs of respiratory depression.

Benzodiazepines and Other Central Nervous System (CNS) Depressants

Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants such as benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, and other opioids, including alcohol, increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.

Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation (see WARNINGS: Life- Threatening Respiratory Depression ).

Serotonergic Drugs

The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system, such as selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), and monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue), has resulted in serotonin syndrome (see PRECAUTIONS: Information for Patients ).

If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue hydrocodone bitartrate and ibuprofen tablets if serotonin syndrome is suspected.

Monoamine Oxidase Inhibitors (MAOIs)

MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma).

If urgent use of an opioid is necessary with MAOIs such as phenelzine, tranylcypromine, linezolid, use test doses and frequent titration of small doses to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression.

The use of hydrocodone bitartrate and ibuprofen tablets are not recommended for patients taking MAOIs or within 14 days of stopping such treatment.

Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics

Agonist/antagonist analgesics such as pentazocine, nalbuphine, butorphanol and buprenorphine may reduce the analgesic effect of hydrocodone bitartrate and ibuprofen tablets and/or precipitate withdrawal symptoms in these patients.

Avoid concomitant use of these drugs.

Muscle Relaxants
Hydrocodone, as well as other opioid analgesics, may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.

Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of hydrocodone bitartrate and ibuprofen tablets and/or the muscle relaxant as necessary.

Anticholinergics

The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.

Monitor patients for signs of urinary retention or reduced gastric motility when hydrocodone bitartrate and ibuprofen tablets are used concomitantly with anticholinergic drugs.

Drugs That Interfere With Hemostasis

Ibuprofen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of ibuprofen and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone.

Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.

Monitor patients with concomitant use of hydrocodone bitartrate and ibuprofen tablets with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), SSRIs, and SNRIs for signs of bleeding (see WARNINGS: Hematologic Toxicity ).

Aspirin

Pharmacodynamic studies have demonstrated interference with the antiplatelet activity of aspirin when ibuprofen 400 mg, given three times daily, is administered with enteric coated low-dose aspirin. The interaction exists even following a once-daily regimen of ibuprofen 400 mg, particularly when ibuprofen is dosed prior to aspirin. The interaction is alleviated if immediate-release low-dose aspirin is dosed at least 2 hours prior to a once daily regimen of ibuprofen; however, this finding cannot be extended to enteric-coated low-dose aspirin [see Clinical Pharmacology/Pharmacodynamics ].

Because there may be an increased risk of cardiovascular events due to the interference of ibuprofen with the antiplatelet effect of aspirin, for patients taking low-dose aspirin for cardioprotection who require analgesics, consider use of an NSAID that does not interfere with the antiplatelet effect of aspirin, or non-NSAID analgesics, where appropriate.

Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS: Gastrointestinal Bleeding, Ulceration, and Perforation ).

Concomitant use of hydrocodone bitartrate and ibuprofen tablets and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS: Hematologic Toxicity ).

ACE-Inhibitors, Angiotensin Receptor Blockers, and Beta-blockers

NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol).

During concomitant use of hydrocodone bitartrate and ibuprofen tablets and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.

In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. Monitor for signs of worsening renal function (see WARNINGS: Renal Toxicity and Hyperkalemia ). These effects are usually reversible.

When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.

Diuretics

Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.

During concomitant use of hydrocodone bitartrate and ibuprofen tablets with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS: Renal Toxicity and Hyperkalemia ).

Digoxin

The concomitant use of ibuprofen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.

During concomitant use of hydrocodone bitartrate and ibuprofen tablets and digoxin, monitor serum digoxin levels.

Lithium

NSAIDs have produced elevations in plasma lithium concentration and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.

During concomitant use of hydrocodone bitartrate and ibuprofen tablets and lithium, monitor patients for signs of lithium toxicity.

Methotrexate

Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).

During concomitant use of hydrocodone bitartrate and ibuprofen tablets and methotrexate, monitor patients for methotrexate toxicity.

Cyclosporine

Concomitant use of hydrocodone bitartrate and ibuprofen tablets and cyclosporine may increase cyclosporine’s nephrotoxicity.

During concomitant use of hydrocodone bitartrate and ibuprofen tablets and cyclosporine, monitor patients for signs of worsening renal function.

NSAIDs and Salicylates

Concomitant use of ibuprofen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS: Gastrointestinal Bleeding, Ulceration, and Perforation).

The concomitant use of ibuprofen with other NSAIDs or salicylates is not recommended.

Pemetrexed
Concomitant use of hydrocodone bitartrate and ibuprofen tablets and Pemetrexed may increase the risk of Pemetrexed associated myelosuppression, renal, and GI toxicity (see the Pemetrexed prescribing information).

During concomitant use of hydrocodone bitartrate and ibuprofen tablets and Pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.

NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of Pemetrexed.

In the absence of data regarding potential interaction between Pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following Pemetrexed administration. 

Risk Summary

Use of drug products containing NSAIDs, including Hydrocodone Bitartrate and Ibuprofen Tablets, during the third trimester of pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including Hydrocodone Bitartrate and Ibuprofen Tablets, in pregnant women starting at 30 weeks gestation (third trimester). Prolonged use of opioid analgesics during pregnancy can cause neonatal opioid withdrawal syndrome (see WARNINGS: Neonatal Opioid Withdrawal Syndrome ). There are no available data with hydrocodone bitartrate and ibuprofen tablets in pregnant women to inform a drug-associated risk for major birth defects and miscarriage. Data from observational studies regarding potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive.

In animal reproduction studies, an increase in the percentage of litters and fetuses with any major abnormality and an increase in the number of litters and fetuses with one or more nonossified metacarpals was observed when the combination of hydrocodone and ibuprofen was administered orally to pregnant rabbits during organogenesis at 1.8 times the maximum daily dose. There are no animal reproductive and developmental toxicology studies with hydrocodone alone.

In published animal reproduction studies testing ibuprofen alone, there were no clear developmental effects at doses up to 1.2 times the maximum recommended human dose (MRHD) in the rabbit and 1.8 times in the MRHD rat when dosed throughout gestation. In contrast, an increase in membranous ventricular septal defects was reported in rats treated on Gestation Days 9 & 10 with 3 times the MRHD. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as ibuprofen, resulted in increased pre- and post-implantation loss (see Data). Based on animal data, advise pregnant women of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Clinical Considerations

Fetal/neonatal adverse reactions

Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth.

Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high-pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly (see WARNINGS: Neonatal Opioid Withdrawal Syndrome ).

Labor and Delivery

Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression.

There are no studies on the effects of hydrocodone bitartrate and ibuprofen tablets during labor or delivery. In animal studies, NSAIDs, including ibuprofen, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth.

Hydrocodone bitartrate and ibuprofen tablets are not recommended for use in women during and immediately prior to labor, when use of shorter-acting analgesics or other analgesic techniques are more appropriate. Opioid analgesics, including Hydrocodone Bitartrate and Ibuprofen Tablets, can prolong labor through actions that temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilatation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression.

Data

Animal Data

Pregnant rabbits were treated with 10, 33, or 95 mg/kg of 1:27 ratio of hydrocodone:ibuprofen (the high dose is 1.8 times the maximum daily dose of both compounds based on surface area) from Gestation Day 5 to 18. The dose of 95 mg/kg of the combination, which also produced maternal toxicity (44% decrease in body weight gain compared to control), resulted in an increase in the percentage of litters and fetuses with any major abnormality and an increase in the number of litters and fetuses with one or more nonossified metacarpals (a minor abnormality).

Pregnant rats were treated with 50, 100, or 166 mg/kg of a 1:27 ratio of hydrocodone:ibuprofen (the high dose is 1.6 times the maximum daily dose of both compounds based on body surface area) from Gestation Day 5 to 15. No reproductive toxicity was noted despite the presence of maternal toxicity in the 100 and 166 mg/kg groups (21% and 60% decrease in body weight gain compared to control).

In a published study, female rabbits given 7.5, 20, or 60 mg/kg ibuprofen (0.15, 0.39, or 1.2 times the maximum recommended human daily dose of 1000 mg of ibuprofen based on body surface area) from Gestation Days 1 to 29, no clear treatment-related adverse developmental effects were noted. This dose was associated with significant maternal toxicity (stomach ulcers, gastric lesions). In the same publication, female rats were administered 7.5, 20, 60, 180 mg/kg ibuprofen (0.07, 0.2, 0.6, 1.8 times the maximum daily dose) did not result in clear adverse developmental effects. Maternal toxicity (gastrointestinal lesions) was noted at 20 mg/kg and above.

In a published study, rats were orally dosed with 300 mg/kg ibuprofen (3 times the maximum human daily dose of 1000 mg based on body surface area) during Gestation Days 9 and 10 (critical time points for heart development in rats). Ibuprofen treatment resulted in an increase in the incidence of membranous ventricular septal defects. This dose was associated with significant maternal toxicity including gastrointestinal toxicity (1 out of 20 animals). In the same study/publication rabbits were dosed on Gestation Day 9, 10 and 11 with 500 mg/kg (9.7 times the maximum human daily dose), and only one incidence each of a membranous ventricular septal defect and gastroschisis was noted in the rabbit fetuses. This dose was also associated with maternal toxicity.

Risk Summary

Hydrocodone is present in human milk. A published lactation study reports variable concentrations of hydrocodone and hydromorphone (an active metabolite) in breast milk with administration of immediate-release hydrocodone to nursing mothers in the early post-partum period. This lactation study did not assess breastfed infants for potential adverse drug reactions.

Limited published literature reports that, following oral administration, ibuprofen is present in human milk at relative infant doses of 0.06% to 0.6% of the maternal weight-adjusted daily dose.

Lactation studies have not been conducted with Hydrocodone Bitartrate and Ibuprofen Tablets, and no information is available on the effects of the drug on the breastfed infant or the effects of the drug on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for hydrocodone bitartrate and ibuprofen tablets and any potential adverse effects on the breastfed infant from hydrocodone bitartrate and ibuprofen tablets or from the underlying maternal condition.

Clinical Considerations

Monitor infants exposed to hydrocodone bitartrate and ibuprofen tablets through breast milk for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of hydrocodone is stopped, or when breastfeeding is stopped

The safety and effectiveness of Hydrocodone Bitartrate and Ibuprofen tablets in pediatric patients below the age of 16 have not been established.

In controlled clinical trials there was no difference in tolerability between patients < 65 years of age and those ≥ 65, apart from an increased tendency of the elderly to develop constipation. However, elderly patients are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and renal adverse reactions as well as possible increased risk of respiratory depression with opioids. In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy (see WARNINGS: Cardiovascular Thrombotic Events, Gastrointestinal Bleeding, Ulceration, and Perforation, Renal Toxicity and Hyperkalemia ).

Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of hydrocodone bitartrate and ibuprofen tablets slowly in geriatric patients  and monitor closely for signs of central nervous system and respiratory depression (see WARNINGS: Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients ).

Both hydrocodone and ibuprofen are known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Following an acute over dosage, toxicity may result from hydrocodone and/or ibuprofen.

Clinical Presentation

Hydrocodone Component

Acute overdose with opioids can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations.

Ibuprofen Component

Symptoms following acute NSAID over dosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred (see WARNINGS: Gastrointestinal Bleeding, Ulceration, and Perforation ). Hypertension, acute renal failure, respiratory depression, and coma have occurred, but were rare (see WARNINGS: Hypertension, Renal Toxicity and Hyperkalemia ).

Treatment of Overdose

In case of overdose, priorities are the re-establishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life-support techniques.

The opioid antagonists, naloxone or nalmefene, are specific antidotes to respiratory depression resulting from opioid overdose. For clinically significant respiratory or circulatory depression secondary to hydrocodone overdose, administer an opioid antagonist. Opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to hydrocodone overdose.

Because the duration of opioid reversal is expected to be less than the duration of action of hydrocodone, carefully monitor the patient until spontaneous respiration is reliably re­ established. If the response to an opioid antagonist is suboptimal or only brief in nature, administer additional antagonist as directed by the product’s prescribing information.

In an individual physically dependent on opioids, administration of the recommended usual dosage of the antagonist will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be begun with care and by titration with smaller than usual doses of the antagonist.

Manage patients with symptomatic and supportive care following an NSAID over dosage. There are no specific antidotes. Consider emesis and/or activated charcoal (60 to 100 grams in adults, 1 to 2 grams per kg of body weight in pediatric patients) and/or osmotic cathartic in symptomatic patients seen within four hours of ingestion or in patients with a large overdose (5 to 10 times the recommended dosage). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding.

For additional information about over dosage treatment contact a poison control center (1-800-222-1222). 

Advise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each prescription dispensed. Patients, families, or their caregivers should be informed of the following information before initiating therapy with hydrocodone bitartrate and ibuprofen tablets and periodically during the course of ongoing therapy.

1.   Addiction, Abuse, and Misuse
Inform patients that the use of Hydrocodone Bitartrate And Ibuprofen Tablets, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death (see WARNINGS: Addiction, Abuse, and Misuse ). Instruct patients not to share hydrocodone bitartrate and ibuprofen tablets with others and to take steps to protect hydrocodone bitartrate and ibuprofen tablets from theft or misuse.

2.   Life-Threatening Respiratory Depression
Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting hydrocodone bitartrate and ibuprofen tablets or when the dosage is increased, and that it can occur even at recommended dosages (see WARNINGS: Life-Threatening Respiratory Depression ). Advise patients how to recognize respiratory depression and to seek medical attention if breathing difficulties develop.

3.   Accidental Ingestion
Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death (see WARNINGS: Life-Threatening Respiratory Depression ). Instruct patients to take steps to store hydrocodone bitartrate and ibuprofen tablets securely and to dispose of unused hydrocodone bitartrate and ibuprofen tablets appropriately as described below.

4.   Interactions with Benzodiazepines and Other CNS Depressants
Inform patients and caregivers that potentially fatal additive effects may occur if hydrocodone bitartrate and ibuprofen tablets are used with benzodiazepines or other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a healthcare provider (see WARNINGS: Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants , PRECAUTIONS: Drug Interactions ).

5.   Serotonin Syndrome
Inform patients that opioids could cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop. Instruct patients to inform their healthcare providers if they are taking, or plan to take serotonergic medications (see PRECAUTIONS: Drug Interactions ).

6.   MAOI Interaction
Inform patients to avoid taking hydrocodone bitartrate and ibuprofen tablets while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking hydrocodone bitartrate and ibuprofen tablets (see PRECAUTIONS: Drug Interactions ).

7.   Adrenal Insufficiency
Inform patients that opioids could cause adrenal insufficiency, a potentially life-threatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms (see WARNINGS: Adrenal Insufficiency ).

8.   Important Administration Instructions
Instruct patients how to properly take HYDROCODONE BITARTRATE AND IBUPROFEN TABLETS. For the short-term (generally less than 10 days) management of acute pain, the recommended dose of hydrocodone bitartrate and ibuprofen tablets are one tablet every 4 to 6 hours, as necessary. Inform patients that the dosage should not exceed 5 tablets in a 24-hour period (see DOSAGE AND ADMINISTRATION ).

9.   Hypotension
Inform patients that hydrocodone bitartrate and ibuprofen tablets may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position) (see WARNINGS: Severe Hypotension ).

10. Anaphylaxis
Inform patients that anaphylaxis has been reported with ingredients contained in Hydrocodone Bitartrate and Ibuprofen Tablets. Advise patients how to recognize such a reaction and when to seek medical attention (see CONTRAINDICATIONS , WARNINGS: Anaphylactic Reactions ).

11. Pregnancy
Neonatal Opioid Withdrawal Syndrome
Inform female patients of reproductive potential that prolonged use of hydrocodone bitartrate and ibuprofen tablets during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated (see Boxed Warning , WARNINGS: Neonatal Opioid Withdrawal Syndrome , PRECAUTIONS: Pregnancy ).

Embryo-Fetal Toxicity
Inform female patients of reproductive potential that hydrocodone bitartrate and ibuprofen tablets can cause fetal harm and to inform the prescriber of a known or suspected pregnancy. Inform pregnant women to avoid use of hydrocodone bitartrate and ibuprofen tablets and other NSAIDs starting at 30 weeks gestation because of the risk of premature closing of the fetal ductus arteriosus (see WARNINGS: Premature Closure of Fetal Ductus Arteriosis , PRECAUTIONS: Pregnancy ).

12. Lactation
Advise nursing mothers to monitor infants for increased sleepiness (more than usual), breathing difficulties, or limpness. Instruct nursing mothers to seek immediate medical care if they notice these signs (see PRECAUTIONS: Nursing Mothers ).

13. Infertility

Inform patients that chronic use of opioids may cause reduced fertility. It is not known whether these effects on fertility are reversible. Advise female patients of reproductive potential who desire pregnancy that NSAIDs, including Hydrocodone Bitartrate And Ibuprofen Tablets, may be associated with a reversible delay in ovulation (see PRECAUTIONS: Carcinogenicity, Mutagenicity, Impairment of Fertility ).

14. Driving or Operating Heavy Machinery
Inform patients that hydrocodone bitartrate and ibuprofen tablets may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication (see WARNINGS: Risks of Driving and Operating Machinery ).

15. Constipation
Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention (see ADVERSE REACTIONS: Clinical Trials Experience ).

16. Cardiovascular Thrombotic Events
Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their healthcare provider immediately (see WARNINGS: Cardiovascular Thrombotic Events ).

17. Gastrointestinal Bleeding, Ulceration, and Perforation
Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their healthcare provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding (see WARNINGS: Gastrointestinal Bleeding, Ulceration, and Perforation ).

18. Hepatotoxicity
Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If these occur, instruct patients to stop hydrocodone bitartrate and ibuprofen tablets and seek immediate medical therapy (see WARNINGS: Hepatotoxicity ).

19. Heart Failure and Edema
Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur (see WARNINGS: Heart Failure and Edema ).

20. Serious Skin Reactions
Advise patients to stop hydrocodone bitartrate and ibuprofen tablets immediately if they develop any type of rash and to contact their healthcare provider as soon as possible (see WARNINGS: Serious Skin Reactions ).

21. Avoid Concomitant use of NSAIDs
Inform patients that the concomitant use of hydrocodone bitartrate and ibuprofen tablets with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy (see WARNINGS: Gastrointestinal Bleeding , Ulceration, and Perforation , PRECAUTIONS: Drug Interactions ). Alert patients that NSAIDs may be present in “over the counter” medications for treatment of colds, fever, or insomnia.

22. Use of NSAIDS and Low-Dose Aspirin
Inform patients not to use low-dose aspirin concomitantly with hydrocodone bitartrate and ibuprofen tabletsuntil they talk to their healthcare provider (see PRECAUTIONS: Drug Interactions ).

23. Ophthalmological Effects
Instruct patients to report any signs of blurred vision or other eye symptoms (see PRECAUTIONS: Ophthalmological Effects ).

24. Disposal of Unused Hydrocodone Bitartrate and Ibuprofen Tablets
Advise patients to flush the unused tablets down the toilet when hydrocodone bitartrate and ibuprofen tablets are no longer needed or to contact the Drug Enforcement Agency (DEA) to find the location of an authorized collector (1-800-882-9539).

HYDROCODONE BITARTRATE AND IBUPROFEN TABLETS    CII

Hydrocodone Bitartrate and ibuprofen Tablets are : A strong prescription pain medicine that contains an opioid (narcotic) and a non-steroidal anti- inflammatory drug (NSAID), that is used to manage short-term (acute) pain, when other pain treatments such as non-opioid pain medicines do not treat your pain well enough or you cannot tolerate them. An opioid pain medicine can put you at risk for overdose and death. Even if you take your dose correctly as prescribed you are at risk for opioid addiction, abuse, and misuse that can lead to death. NSAIDs are used to treat pain, redness, swelling, and inflammation.

Important information about Hydrocodone Bitartrate And Ibuprofen Tablets:   G et emergency help right away if you take too much Hydrocodone Bitartrate And Ibuprofen Tablets (overdose). When you first start taking Hydrocodone Bitartrate and Ibuprofen Tablets, when your dose is changed, or if you take too much (overdose), serious or life-threatening breathing problems that can lead to death may occur. Taking Hydrocodone Bitartrate and Ibuprofen Tablets with other opioid medicines, benzodiazepines, alcohol, or other central nervous system depressants (including street drugs) can cause severe drowsiness, decreased awareness, breathing problems, coma, and death. Never give anyone else your Hydrocodone Bitartrate and Ibuprofen Tablets. They could die from taking it. Store Hydrocodone Bitartrate and Ibuprofen Tablets away from children and in a safe place to prevent stealing or abuse. Selling or giving away Hydrocodone Bitartrate and Ibuprofen Tablets are against the law. Hydrocodone Bitartrate And Ibuprofen Tablets contains an NSAID. NSAIDs can cause serious side effects, including: Increased risk of a heart attack or stroke that can lead to death. This risk may happen early in treatment and may increase: with increasing doses of medicine containing NSAIDs with longer use of medicine containing NSAIDs Do not take NSAIDS right before or after a heart surgery called a “coronary artery bypass graft (CABG).” A v o id taking NSAIDS after a recent heart attack, unless your healthcare provider tells you to. You may have an increased risk of another heart attack if you take NSAIDs after a recent heart attack. Increased risk of bleeding, ulcers, and tears (perforation) of the esophagus (tube leading from the mouth to the stomach), stomach and intestines: any time during us Without warning symptoms that may cause death Th e risk of getting an ulcer or bleeding increases with: past history of stomach ulcers, or stomach or intestinal bleeding with use of NSAIDs increasing doses of NSAIDS longer use of NSAIDS smoking drinking alcohol taking medicines called “corticosteroids,” “anticoagulants,” “SSRIs,” or “SNRIs” older age poor health advanced liver disease bleeding problems

Do not take Hydrocodone Bitartrate And Ibuprofen Tablets: if you have severe asthma, trouble breathing, or other lung problems. if you have a bowel blockage or have narrowing of the stomach or intestines. if you have had an asthma attack, hives, or other allergic reaction with aspirin, other NSAIDs, or opioid medicine. right before or after heart bypass surgery.

Before taking Hydrocodone Bitartrate And Ibuprofen Tablets, tell your healthcare provider if you have a history of:   •    head injury or seizures                                       •    liver, kidney, or thyroid problems •    problems urinating                                              •    pancreas or gallbladder problems •    high blood pressure                                            •    asthma •    abuse of street or prescription drugs, alcohol addiction, or mental health problems. T ell your healthcare provider if you are: Pregnant o r planning to become pregnant. Talk to your healthcare provider if you are considering taking Hydrocodone Bitartrate and Ibuprofen Tablets during pregnancy. Prolonged use of Hydrocodone Bitartrate and Ibuprofen Tablets during pregnancy can cause withdrawal symptoms in your newborn baby that could be life-threatening if not recognized and treated. You should not take NSAIDs after 29 weeks of pregnancy. Breastfeeding o r planning to breastfeed. Hydrocodone Bitartrate and Ibuprofen Tabletspasses into breast milk and may harm your baby. taking prescription or over-the-counter medicines, vitamins, or herbal supplements. Taking Hydrocodone Bitartrate and Ibuprofen Tablets with certain other medicines can cause serious side effects that could lead to death.

W h en taking Hydrocodone Bitartrate And Ibuprofen Tablets: Do not change your dose. Take Hydrocodone Bitartrate and Ibuprofen Tablets exactly as prescribed by your healthcare provider. Use the lowest dose possible for the shortest time needed. Take your prescribed dose every 4 to 6 hours, as needed. Do not take more than your prescribed dose. If you miss a dose, take your next dose at your usual time. Call your healthcare provider if the dose you are taking does not control your pain. If you have been taking Hydrocodone Bitartrate and Ibuprofen Tablets regularly, do not stop taking it without talking to your healthcare provider. After you stop taking Hydrocodone Bitartrate and Ibuprofen Tablets, flush any unused tablets down the toilet or contact the Drug Enforcement Agency (DEA) to find the location of an authorized collector (1-800-882­9539) after you stop taking Hydrocodone Bitartrate and Ibuprofen Tablets.

W h ile taking Hydrocodone Bitartrate And Ibuprofen Tablets DO NOT: •    drive or operate heavy machinery, until you know how it affects you. Hydrocodone Bitartrate And Ibuprofen Tablets can make you sleepy, dizzy, or lightheaded. •    drink alcohol or use prescription or over-the-counter medicines that contain alcohol. Using products containing alcohol during treatment with Hydrocodone Bitartrate And Ibuprofen Tablets may cause you to overdose and die.

T h e possible side effects of Hydrocodone Bitartrate And Ibuprofen Tablets: constipation, diarrhea, gas, heartburn, nausea, sleepiness, vomiting, tiredness, headache, dizziness, abdominal pain, heart attack, stroke, new or worse high blood pressure, heart failure, liver problems including liver failure, kidney problems including kidney failure, bleeding and ulcers in the stomach and intestine, low red blood cells (anemia), life-threatening skin reactions, life- threatening allergic reactions, asthma attacks in people who have asthma. Call your healthcare provider if you have any of these symptoms and they are severe. G et emergency medical help if you have:   •   trouble breathing or shortness of breath         •  agitation •   fast heartbeat                                                  •  high body temperature •   chest pain                                                       •  trouble walking •   swelling of your face, tongue, or throat           •  stiff muscles •   extreme drowsiness                                        •  mental changes such as confusion •   lightheadedness when changing positions     •  weakness in one part or side of your body •   a fainting spell                                                 •  slurred speech S to p Hydrocodone Bitartrate And Ibuprofen Tablets and call your healthcare provider right away if you have any of the following symptoms:   •    nausea                                                    •    flu-like symptoms •    more tired or weaker than usual             •    vomit blood •    diarrhea                                                  •    there is blood in your bowel movement or it is black and sticky like tar •    itching                                                     •    unusual weight gain •    your skin or eyes look yellow                  •    skin rash or blisters with fever          •    indigestion or stomach pain                    •    swelling of the arms and legs, hands and feet These are not all the possible side effects of Hydrocodone Bitartrate And Ibuprofen Tablets. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. For more information go to dailymed.nlm.nih.gov. Oth er information:   •    Aspirin is an NSAID medicine, but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines. •    Do not take other NSAID medicines, even those sold in lower doses without a prescription (over-the-counter) while taking Hydrocodone bitartrate and ibuprofen tablets. NSAIDs may be present in over-the-counter medications for treatment of colds, fever, or insomnia.

Distributed by:
Aurobindo Pharma USA, Inc.
279 Princeton-Hightstown Road
East Windsor, NJ 08520

Revised:03/2019

Each Hydrocodone Bitartrate and Ibuprofen tablet contains:
Hydrocodone Bitartrate, USP  7.5 mg
Ibuprofen, USP    200 mg

Hydrocodone Bitartrate and Ibuprofen tablets are supplied in a fixed combination tablet form for oral administration. Hydrocodone Bitartrate and Ibuprofen tablets combines the opioid analgesic agent, hydrocodone bitartrate, with the nonsteroidal anti-inflammatory (NSAID) agent, ibuprofen.

Hydrocodone bitartrate is a semisynthetic opioid analgesic. Its chemical name is: 4,5 α-epoxy-3-methoxy-17-methylmorphinan-6-one tartrate (1:1) hydrate (2:5). Its chemical formula is: C ₁₈H ₂₁NO ₃•C ₄H ₆O ₆•2½H ₂O, and the molecular weight is 494.50. Its structural formula is:

[image: MM1]

Ibuprofen is a non-steroidal anti-inflammatory agent [non-selective COX inhibitor] with analgesic and antipyretic properties. Its chemical name is: (±)-2-(p-isobutylphenyl) propionic acid. Its chemical formula is: C13H18O2, and the molecular weight is: 206.29. Its structural formula is:

[image: MM2]

Inactive ingredients in Hydrocodone Bitartrate and Ibuprofen tablets include: anhydrous lactose, colloidal silicon dioxide, croscarmellose sodium, lactose monohydrate, magnesium stearate, sodium starch glycolate, sodium lauryl sulfate, polysorbate 80, hypromellose, titanium dioxide and polyethylene glycol.

[image: img_8909cfeb-e925-82b5-e053-2995a90a71b8]

Hydrocodone Bitartrate and Ibuprofen Tablets, 7.5 mg/200 mg are white to off-white, round, film coated tablets, debossed with “U13” on one side and plain on the other side.

Bottles of 10                  NDC 13107-004-11
Bottles of 100                NDC 13107-004-01
Bottles of 500                NDC 13107-004-05
Bottles of 1,000             NDC 13107-004-99

Storage

Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].

Dispense in a tight, light-resistant container. Keep this and all medication out of the reach of children.

A Schedule C-II Controlled Drug Substance.

Dispense with Medication Guide available at www.aurobindousa.com/product-medication-guides

Distributed by:
Aurobindo Pharma USA, Inc.
279 Princeton-Hightstown Road
East Windsor, NJ 08520

Revised:03/2019